Dynamic Post-Translational Control of HDAC Activity in Breast Cancer and Implications for Drug Discovery
thesisposted on 25.07.2018, 00:00 by Thomas Hanigan
Histone deacetylase (HDAC) activity is regulated by formation of co-regulator complexes and post-translational modification. Whether these mechanisms are transformed in cancer and how this affects the binding and selectivity of HDAC inhibitors (HDACi) is unclear. In this work, we developed a set of methods, based on photoreactive HDAC inhibitor probes (PRPs), to determine how post-translational regulation of HDAC activity affects inhibitor binding in situ. Using these methods we show that phosphorylation of several HDAC isoforms plays a key role in regulating inhibitor binding and selectivity in a cell-typed dependent manner. Of particular importance, we find that phosphorylation of HDAC3 by c-Jun N-terminal kinase (JNK) plays an important role in regulating HDAC3-inhibitor binding and enzyme activity in aggressive triple-negative breast cancer cell lines (TNBC), suggesting this enzyme could be a pertinent target for this disease state. We also show that several breast cancer cell lines exert a post-translational feedback mechanism on HDAC activity in response to potent HDAC inhibitors and provide evidence that this is plays an important role in HDACi mechanism of action.